Fluorine is the element with highest electronegativity. Due to its size and unique electronic properties, fluorine quite often imparts significantly different (often beneficial) properties to organic molecules. (Kirsch, Peer. 2004, Modern Fluoroorganic Chemistry Synthesis, Reactivity, Applications. Weinheim Wiley-VCH). It is widely known that the incorporation of fluorine into organic molecule has a significant effect on its physical, chemical, and biological properties (Welch, J. T. Tetrahedron 1987, 43, 3123). These changes in properties make them suitable for diverse applications in material science, agrochemistry, as well as in pharmaceutical industry (Robert Millar, Rituparna Saha, Future Medicinal Chemistry, 2009, 1(5) 777-779).
The α-fluoromethyl aryl ketones are often found in bioactive molecules or are often used as building blocks for other organofluorine compounds. For example, it has been well recognized that the electron withdrawing effect of fluorine atom can increase the susceptibility of the carbonyl group to hydration. In fact, this property has been exploited in the design of inhibitors of hydrolytic enzyme. See, for example, M. R. Heinrich, Tetrahedron Lett. 48 (2007), 3895-3908; R. Katoch-Rouse et al., J. Med. Chem., 46 (2003), 642-645; B. Zajc et al., J. Org. Chem., 55 (1990), 1099-1102; D. Schirlin et al., Med. Chem. Lett., 3 (1993), 253-258. Due to their importance, efficient and practical synthetic strategies towards α-fluoromethyl aryl ketones have long been pursued.
In general, there are mainly two synthetic approaches to α-fluoromethyl aryl ketones. T. Furuya et al., Curr. Opin. Drug Discovery Development, 11 (2008), 803-819. The first approach involves the introduction of fluorine atom into non-fluorinated substrate with electrophilic fluorinating reagents, such as N-fluorosulfonimides or Selectfluor. See, for example, W. E. Barnette, J. Am. Chem. Soc. 106 (1984), 452-454; P. Kwiatkowski et al., J. Am. Chem. Soc., 133 (2011) 1738-1741; N. Ahlsten et al., Synthesis, (2011) 2600-2608; E. Fuglseth et al., Tetrahedron, 64 (2008), 7318-7323; S. Stavber et al., Chem. Commun., (2000), 1323-1324; W. Peng et al., J. Org. Chem., 70 (2005), 5760-5763; T. H. K. Thvedt et al., Tetrahedron, 65 (2009) 9550-9556. Unfortunately, these reagents are highly expensive for use in a large scale reaction and/or are difficult to prepare due to the need for the elemental fluorine. The second approach towards α-fluromethyl aryl ketone is the nucleophilic substitution of α-bromomethyl aryl ketones with fluorine using KF/Ph3SnF. See, for example, M. Makosza et al., Tetrahedron Lett., 45 (2004), 1385-1386; KF/18-crown-6 (C. L. Liotta et al., J. Am. Chem. Soc., 96 (1974), 2250-2252; L. Fitjer, Synthesis, 3 (1977) 189-191; KF/PEG-1000 (J. Leroy, J. Org. Chem., 46 (1981), 206-209); KF/PEG-400 or TBAF:3H2O, and ZnF2/KF (Z. Z. Chen et al., J. Fluorine Chem., 131 (2010), 340-344). However, these combinations of fluorinating reagents have low solubility, thereby limiting their usefulness in a large scale or continuous processes.
Hydrogen fluoride is the most basic nucleophilic fluorinating reagent. A. Bowers et al., J. Am. Chem. Soc., 1960, 82, 4001-4007; A. Bowers et al., J. Am. Chem. Soc., 1960, 82, 4007-4012. Unfortunately, due to difficulties associated with handling hydrogen fluoride, its general applicability as a fluorinating agent is severely limited. Other fluorinating reagents include pyridinium poly(hydrogen fluoride) (i.e., Py.nHF, where n is in the range from 1-10) (G. A. Olah et al., J. Org. Chem, 1979, 44, 3842-3881; D. Y. Chi et al., J. Org. Chem., 1987, 52, 658-664) and triethylamine trihydrogen fluoride (Et3N—3HF) (G. Alyemhe et al., Synthesis, 1987, 562-564; M. Tamura et al., Synthesis, 1995, 515-517). However, these reagents also require careful handling as they fume in air.
Therefore, there is a need for relatively safe and/or non-fuming fluorinating reagent to produce α-fluoromethyl aryl ketones.